Abstract

The neuropeptide urocortin 2 (Ucn2) and its receptor corticotropin releasing hormone receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance and glucose metabolism. We investigated a modified Ucn2 peptide as a potential therapeutic agent for the treatment of obesity and insulin resistance, with a specific focus on skeletal muscle. High fat-fed mice (C57Bl/6J) were injected daily with a PEGylated Ucn2 peptide (Compound A) at 0.3 mg/kg subcutaneously for 14 days. Compound A reduced body weight, food intake, whole-body fat mass, and intramuscular triglycerides as compared with vehicle-treated controls. Furthermore, whole-body glucose tolerance was improved by Compound A treatment, with increased insulin-stimulated Akt phosphorylation at Ser473 and Thr308 in skeletal muscle, concomitant with increased glucose transport into extensor digitorum longus and gastrocnemius muscle. Mechanistically, this is linked to a direct effect on skeletal muscle, as ex vivo exposure of soleus muscle from chow-fed lean mice to Compound A increased glucose transport and insulin signaling. Moreover, exposure of GLUT4-Myc labelled L6 myoblasts to Compound A increased GLUT4 trafficking. Our results demonstrate that modified Ucn2 peptides may be efficacious in the treatment of type 2 diabetes by acting as an insulin sensitizer in skeletal muscle.